Clinical bone marrow transplantation is an important therapeutic treatment for several diseases including high risk leukemia, aplastic anemia, and severe combined immunodeficiency. In addition, there is a wide range of metabolic and genetic disorders that can potentially be corrected by this approach. However, the usefulness of marrow transplantation is currently limited by several important risk factors, the principal one being graft-versus-host disease (GVHD), an often times lethal complication which occurs in a high proportion of transplants.
The risk of GVHD can be reduced by HLA matching of the marrow donor and recipient, with a matched sibling being the primary choice. Yet, less than 30% of the patients in North America have an HLA-matched sibling, and therefore must seek suitable unrelated HLA-matched donors from the National Marrow Donor Program. The probability of finding an unrelated HLA-matched donor is currently on the order of 30-40% and depend on the total number of donors registered. In both related and unrelated HLA-matched transplant situations, the risk of GVHD is still quite high due to disparity of non-HLA multiple minor histocompatibility (H) antigens. GVHD is somewhat higher in unrelated cases, as this increases the probability of differences at these loci.
Mature donor T cells contaminating the marrow inoculum are responsible for GVHD. Several studies have shown that depletion of these T cells significantly diminishes the incidence of disease. However, the elimination of donor T cells has also resulted in a greater incidence of leukemic relapse. It seems important to provide at least some level of T cell immunocompetency in these completely immunocompromised patients to not only combat residual leukemia cells but also to counter opportunistic infections. In this respect, the same GVHD-reactive donor T cells may be important for targeting leukemia cells expressing the same host allogeneic histocompatibility antigens. Therapeutic approaches that could ameliorate the pathogenic tissue destruction accompanying GVHD, particularly in the gut and skin, but that would allow for continued anti-leukemia activity would greatly benefit marrow transplant patients.
Immediate allergic responses, also referred to as type 1 hypersensitivity reactions, are mediated through the interaction of immunoglobulin E (IgE) with the .alpha.-chain of its high affinity Fc receptor, Fc.epsilon.R1. The binding of a multivalent allergen to an IgE-Fc.epsilon.R1complex initiates a cross-linking of the receptor and consequent cellular activation. These high affinity receptors are found primarily on mast cells and basophils. When activated by an allergen, these cells respond by releasing histamine, eicosanoids and cytokines.
In addition to its high affinity Fc receptor, IgE binds to a low affinity receptor, the Fc.epsilon.R2, which is found on B cells, T cells, macrophages, NK cells, eosinophils, platelets, follicular dendritic cells as well as several other cell types. Activation of the Fc.epsilon.R2 has been implicated in IgE-dependent cell cytotoxicity (ADCC) as well as in allergic inflammation.
Many different fine mapping studies have been conducted on the binding of the IgE to its Fc receptors. The consensus mapping data is confirmed by a recent study by Nissim et al. (1993) J. Immunol. 150: 1365-1374, which is incorporated herein by reference, showing that the binding activity for both the high and low affinity receptors resides within the C.epsilon.3 (the third constant domain) of the IgE. Data show that the species specific binding of IgE to the Fc.epsilon.R1 is contained within the first 16 amino acids of the CE3, whereas no species specific binding is observed in the same region with respect to binding the Fc.epsilon.R2.
There is a need for compounds and methods which can inhibit IgE-Fc.epsilon.R1 interaction. IgE-Fc.epsilon.R1 interaction is associated with immediate allergic reactions. There is a need for compounds and methods which can inhibit mast cell and basophil activity that results from IgE-Fc.epsilon.R1 interaction. Mast cell and basophil activity linked to IgE-Fc.epsilon.R1 interaction is associated, for example with reactions to allergens and GVHD. Identification of compounds that inhibit the IgE-Fc.epsilon.R1 interaction can be used in methods of treating allergies and GVHD.